Association of PAK4 expression with overall survival in patients with non-small cell lung cancer (NSCLC).
Authors: Hirva Mamdani, Sharon Wu, Erin Morgan, Husain Yar Khan, Chadi Nabhan, Jorge J. Nieva, Wolfgang Michael Korn, Dipesh Uprety, Sonam Puri, Hina Khan, Luis E. Raez, Hossein Borghaei, Balasz Halmos, Patrick C. Ma, Gilberto Lopes, Stephen V. Liu, Asfar S. Azmi
Journal: Journal of Clinical Oncology (2022)

e21149 Background: P21-activated kinase 4 (PAK4) is a crucial effector of the Rho GTPases. It acts as a regulatory switch that controls a wide range of cellular functions and plays a pivotal role in cancer progression and metastasis. Very little is known about the expression and prognostic value of PAK4 in NSCLC. Methods: 17,689 NSCLC tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes, or WES NovaSeq), immunohistochemistry (IHC), and whole transcriptome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was analyzed by IHC (Dako 22c3; PD-L1 positive: TPS &gt;1%). TMB was measured by counting all somatic mutations found per tumor (TMB-high: &gt;10 mutations/MB). Tumors with PAK4-high (H) and PAK4-low (L) expression were classified as those in top quartile and bottom 3 quartiles, respectively. Immune cell infiltrates were calculated by Quantiseq. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value &lt; 0.05). Survival was extracted from insurance claims data and calculated from the time of tissue collection to the last contact using Kaplan-Meier estimates. Results: There was no difference in median age, gender, smoking status, and histologic distribution between PAK-H and PAK-L tumors. Compared to PAK4-L, the PAK4-H was associated with higher frequency of co-mutations in TP53 (76.3% vs 63.9%, p &lt; 0.0001) and RB1 (13.6% vs 8.1%, p &lt; 0.0001). PAK4-H tumors were associated with greater genomic loss of heterozygosity (24.1% vs 16.4%, p &lt; 0.0001), and expression of immune checkpoint genes ( LAG3, PDCD1, PDCD1LG2, CD274, IDO1, CTLA4, CD80, HAVCR2; p &lt; 0.05). KRAS (including KRAS G12C) , BRAF, STK11, and EGFR mutations, and ALK and ROS1 fusions were less frequent in PAK4-H tumors (p &lt; 0.001). A greater proportion of PAK4-H tumors were TMB-H (40.3% vs 33.3%, p &lt; 0.0001) and PD-L1 negative (48.2% vs 40.8%, p &lt; 0.001). PAK4-H tumors had lower infiltration of B cells, M1/M2 macrophages, CD8+ T-cells, and Tregs (p &lt; 0.001). Overall survival (OS) was inferior among patients with PAK4-H tumors (median, 14.9 vs 21.5 months, HR = 1.28, 95% CI, 1.21-1.36, p &lt; 0.001), which was driven by adenocarcinoma histology. Survival with immunotherapy was also inferior in patients with PAK4-H adenocarcinoma (median, 23.6 vs 30.3 months, HR = 1.23, 95% CI, 1.02-1.48, p = 0.03), but not squamous cell carcinoma. A similar trend in survival was noted in patients who received EGFR- and ALK inhibitors. Conclusions: PAK4-H expression in NSCLC is associated with a higher frequency of alterations predisposing to genomic instability, differentially modulated immune phenotype, and a lower frequency of actionable genomic alterations. Patients with PAK4-H adenocarcinoma have inferior OS, and survival with immunotherapy and targeted therapy. PAK4-H expression defines a subgroup of patients with un unmet need for novel treatment strategies.